The Synthesis/Medicinal Chemistry Core (SynCore) will provide enabling technology vital to this NOVEL SMALL-MOLECULE THERAPIES FOR CF program project. The overall goal of this program is the discovery of novel CF-relevant small-molecules which serve as potentiators of mutant CFTRs, correctors deltaF508-CFTR cellular misprocessing, CFTR inhibitors, enhancers of non-viral gene delivery, resources for correlation between nasal PDs and chloride transport cultured cells from CF subjects, antimicrobials, aquaporin-based enhancers of gland fluid secretion, CFTR activators to enhance alveolar fluid clearance, inhibitors of glandular mucin secretion, resources to chronically inhibit CFTR function in pigs, reagents useful in defining the role of ASL in innate immune defense in CF, reagents useful in defining the role of defective airway submucosal gland secretion in CF lung disease, and hit-to-lead discovery libraries for high-throughput screening. SynCore will figure prominently in this program's efforts to realize these objectives by preparing lead discovery libraries designed to explore hits provide by high-throughput screening and providing study-relevant quantities of the lead compounds required for the studies outlined in the PROJECTs2. The SynCore specific aims are to (1) prepare chemically pure, structurally characterized small-molecule HIT and LEAD compounds for application by the PROJECTS and the COREs and (2) prepare hit-to-lead discovery libraries designed to structurally explore hits identified by high-throughput screening.